Ligand-directed Selectivity in Copper-catalysed Allylic Amination

The Dial-a-Molecule network action on “Applying Statistical Methods to Chemistry Research” supported the establishment of a new collaboration between Prof. Andrei Malkov (AM) at Loughborough University, who leads a group of synthetic chemists, and Dr Natalie Fey (NF) at the University of Bristol, an expert in computational studies of organometallic catalysts and statistical data analysis. The project sought to explore whether data analysis and mechanistic calculations can support the experimental optimisation of a copper-catalysed reaction. The ligands screened previously by AM were characterised in terms of calculated ligand descriptors based on prior work at Bristol and the resulting data were processed into a map of relevant ligand space by statistical analysis. With only limited insights into the copper coordination chemistry throughout the reaction, substrate, intermediates and product were also considered, with the map highlighting that these might compete with ligands for coordination sites. This was explored further by calculated binding energies and extensive computational mechanistic studies, considering both metal-free and metal-catalysed pathways. Experimental screening of ligands, substrates and different reaction conditions was used to confirm the involvement of copper complexes in the catalysis, but produced no further hits for the desirable final reduction step. The calculated data and statistical analyses strongly suggest that the mechanism of copper catalysis needs to be studied in greater detail before reliable reaction optimisation and computational prediction can be achieved, and the project team are planning to publish these results and seek additional funding for such a study in the future